The present invention relates to a novel process for producing quinazoline compounds that are useful in therapy. More specifically, the compounds are useful in the treatment of benign prostatic hyperplasia.
International Patent Application WO 98/30560 discloses a number of substituted quinoline and quinazoline compounds of formula (I), and their pharmaceutically acceptable salts, which are indicated in the treatment of benign prostatic hyperplasia: 
wherein
R1 represents C1-4 alkoxy optionally substituted by one or more fluorine atoms;
R2 represents H or C1-6 alkoxy optionally substituted by one or more fluorine atoms;
R3 represents a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally substituted by one or more groups selected from halogen, C1-4 alkoxy, C1-4 alkyl and CF3;
R4 represents a 4-, 5-, 6-, or 7-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C1-4 alkyl, C1-4 alkoxy, halogen, CONR8R9, SO2NR8R9, (CH2)bNR8R9 and NHSO2(C1-4 alkyl), and when S is a member of the ring system, it may be substituted by one or two oxygen atoms;
R8 and R9 independently represent H or C1-4 alkyl, or together with the N atom to which they are attached they may represent a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S;
b represents 0, 1, 2 or 3;
X represents CH or N; and
L is absent,
or represents a cyclic group of formula Ia, 
in which N is attached to the 2-position of the quinoline or quinazoline ring;
A is absent or represents CO or SO2;
Z represents CH or N;
m represents 1 or 2, and in addition, when Z represents CH, it may represent 0; and
n represents 1, 2 or 3, provided that the sum of m and n is 2, 3, 4 or 5;
or represents a chain of formula Ib, 
in which N is attached to the 2-position of the quinoline or quinazoline ring;
Axe2x80x2 and Zxe2x80x2 have the same significance as A and Z above, respectively;
R6 and R7 independently represent H or C1-4 alkyl; and
p represents 1, 2 or 3, and in addition, when Zxe2x80x2 represents CH, it may represent 0.
The compounds of formula (I) in which X=N and L is absent are of particular interest. Of these compounds, 4-amino-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-6,7-dimethoxy-5-(2-pyridyl)quinazoline is of special interest.
According to WO 98/30560, the compounds of formula (I) can be produced by a number of processes. However, none of these processes involves the condensation of the two main parts of the molecule in a convergent synthesis and each process suffers disadvantages. For example, 4-amino-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-6,7-dimethoxy-5-(2-pyridyl)quinazoline (the compound of Example 19 in WO 98/30560) is prepared according to the following scheme: 
The routes described in WO 98/30560 suffer the disadvantage that they involve the use of tributyl stannyl pyridine in combination with copper iodide and tetrakis (triphenylphosphine) palladium. One problem of this route is that the tributyl stannyl pyridine is expensive to purchase. The compound is toxic and there are issues of worker safety and concerning the environment. After use, spent reactants are difficult and expensive to dispose of because of the adverse effects organotin compounds have on their surroundings. A further problem with the prior art process is its lack of convergency. A number of synthetic steps are required to produce the quinazoline compounds in the disclosed processes, with each synthetic step leading both to a reduction in yield and increasing the possibility of competing side reactions. Thus the conventional reaction requires effort to purify the product and may not give an optimal yield.
A further problem with the prior art process of WO 98/30560 is that large pebble-like aggregates are formed in the reactor during the reaction. The identity of these aggregates is not clear but they are believed to be formed of inorganic material derived from the various inorganic additives used during the reaction such as lithium chloride and copper iodide. In this process, there is the risk that the pebble-like aggregates could crack the reactor causing leakage of the reaction medium and the hazard of fire or poisoning. At the very least there is the problem that the reaction leads to scratching of the interior of the reaction vessel thus causing premature wearing of the vessel, poor heat dissipation in the mixture or blocking.
It is an aim of the present invention to provide a synthetically efficient process for the production of quinazoline derivatives which avoids the problems of the prior art process. It is also an aim to provide a process in which the convergency (ie the bringing together of synthetic fragments) is maximised. It is thus an aim to provide a route to the compounds of formula (I), which offers an improved yield relative to the existing routes. It is a further aim of the process of the present invention to avoid the use of organotin compounds on account of their hazardous nature. It is a further aim of the present invention to provide a process, which minimizes the number of synthetic steps required and which avoids the problem of competing reactions and/or the disposal of hazardous materials.
Accordingly, the present inventors have now found an improved route to the preferred quinazoline derivatives of formula (I) above which overcomes many of the disadvantages of the prior art.
According to the present invention, there is provided a process for the production of a compound of formula (A) or a pharmaceutically acceptable salt or solvate thereof: 
wherein:
R1 represents C1-4 alkoxy optionally substituted by one or more fluorine atoms;
R2 represents H or C1-6 alkoxy optionally substituted by one or more fluorine atoms;
R3 represents a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally substituted by one or more groups selected from halogen, C1-4 alkoxy, C1-4 alkyl and CF3;
R4 is a 4-, 5-, 6-, or 7-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C1-4 alkyl, C1-4 alkoxy, halogen, CONR8R9, SO2NR8R9, (CH2)bNR8R9 and NHSO2(C1-4 alkyl), and when S is a member of the ring system, it may be substituted by 1 or 2 oxygen atoms;
the process comprising condensing a compound of formula (B) 
wherein
R1 to R3 are as defined above;
with a compound of formula (C): 
wherein
R5 and R6 taken together with the N atom to which they are attached represent a 4-, 5-, 6-, or 7-membered N-containing heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C1-4 alkyl, C1-4 alkoxy, halogen, CONR8R9, SO2NR8R9, (CH2)bNR8R9 and NHSO2(C1-4 alkyl), and when S is a member of the ring system, it may be substituted by 1 or 2 oxygen atoms;
R8 and R9 independently represent H or C1-4 alkyl, or together with the N atom to which they are attached they may represent a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S; and
b represents 0, 1, 2 or 3;
and where necessary or desired, converting the resulting compound of formula (I) into a pharmaceutically acceptable salt or solvate, or converting the resulting salt or solvate into a compound of formula (I).
Preferably R1 represents methoxy.
Preferably R2 represents methoxy.
Preferably R3 represents an aromatic heterocyclic ring. More preferably, R3 represents pyridinyl, pyrimidinyl, thienyl, furanyl or oxazolyl. Most preferably R3 represents 2-pyridinyl or 2-pyrimidinyl, the former being especially preferred.
Preferably R4 represents a saturated 6-membered N-containing ring which is fused to an optionally substituted benzene or pyridine ring. More preferably, R4 represents a tetrahydroisoquinoline ring system which is optionally substituted. Most preferably, R4 is 5-methylsulfonylaminotetrahydroisoquinoline.
Most preferably, the process is used to prepare 4-amino-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-6,7-dimethoxy-5-(2-pyridyl)quinazoline.
Preferably the reaction is carried out in a polar aprotic solvent. The polar aprotic solvent is preferably dimethylsulfoxide.
Preferably the reaction is carried out in the presence of a base. More preferably, the base is an alkali metal carbonate. Most preferably, the base is caesium carbonate.
Compounds of formula (C), as defined above, may be formed by reaction of a compound of formula (E),
HCl.HR4xe2x80x83xe2x80x83(E)
wherein R4 is as defined above,
with a compound of formula (F), 
or a compound of formula (X), 
as described in Examples 2 and 2A below. Compounds of formula (E) may be prepared as described in WO 98/30560.
N-(2-amidino-1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide hydrochloride is of particular interest.
Preferably, the reaction is carried out in the presence of an aqueous base, such as aqueous sodium hydroxide; or an organic base, such as diisopropylethylamine.
In another aspect of the invention, there is provided a process wherein the compound of formula (B), as defined above, is formed by reaction of the compound of formula (D): 
wherein R1 and R2 are as defined above;
with a pyridine derivative.
The pyridine derivative may be a pyridyl boronate. In this case, the reaction is preferably carried out in a polar aprotic solvent, such as dioxane. Preferably, the reaction is carried out at the reflux temperature of the solvent. Preferably, the reaction is carried out in the presence of a catalyst. More preferably, the catalyst is a palladium (0) catalyst. The pyridyl boronate may be used xe2x80x9cdampxe2x80x9d in the reaction, for example, it may be used when 50% xe2x80x9cwetxe2x80x9d with THF and dioxane.
A pyridyl boronate of particular interest is obtainable by reacting 2-bromopyridine with triisopropylborate in a solvent such as THF in the presence of a base such as n-butyllithium [see Examples 1(b) and 1A(a) below]. This pyridyl boronate is not readily analyzed. However, it is thought that its structure is as follows: 
Alternatively, the compound of formula (D) is treated initially with zinc to produce a species containing a xe2x80x94Znxe2x80x94I group (known as a xe2x80x9czincatexe2x80x9d). In this case, the preferred pyridine derivative is a bromopyridine, for example 2-bromopyridine. In this case, the reaction is preferably carried out in a solvent such as THF. Preferably, the activation step and the reaction are carried out above room temperature. Preferably, the reaction is carried out in the presence of a catalyst. More preferably, the catalyst is a palladium (II) catalyst.
Most preferably, the process is used to prepare 6-fluoro-3,4-dimethoxy-2-(2-pyridyl)benzonitrile.
The invention further provides a process for the production of a compound of formula (A), as defined above, wherein the starting compound of formula (B) is prepared by methods also forming part of the invention.
The invention further provides the intermediate compounds of formulae (B) and (C), as defined above.
The invention is illustrated by the following examples. The following abbreviations may be used:
DCM=dichloromethane
DMF=dimethylformamide
DMSO=dimethylsulfoxide
mins=minutes
THF=tetrahydrofuran